Potentiation of 3-(4-Amino-2-Methyl-5-Pyrimidinyl) Methyl-1-(2-Chloroethyl)-Nitrosourea Cytotoxicity in Resistant Human Glioma Cell by Pretreatment with 5-(3-Methyl-1-Triazeno) Imidazole-4-Carboxamide
In our previous studies, we reported the results that O6-alkylguanine DNA alkyltransferase (O6-AT) plays an important role in determining the cellular resistance to treatment with chloroethylnitrosourea (CENU) [1–3]. The mechanism of cellular resistance has not been fully understood, but it is clear that O6-AT repairs O6-chloroethylguanine before it can rearrange to form the DNA interstrand cross-link [4–5], and this results in cellular resistance to the cytotoxic effects of CENUs. O6-AT also prevents the induction of sister chromatid exchanges (SCEs) by CENUs, since the increased induction of SCEs is due to higher levels of DNA interstrand cross-links [1,2,6]. The reduction of O6-AT activity in tumor cells which are resistant to CENUs may be used to improve the clinical effectiveness of CENUs, since this activity protects the cytotoxic effects of these agents. This has been approached by pretreatment with a monofunctional methylating agent [2,7,8]. 5-(3-dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC) is a chemotherapeutic agent used primarily to treat malignant melanoma, sarcoma, and lymphoma. DTIC requires metabolic activation through oxidative N-demethylation leading to the formation of the N-demethyl derivative, 5-(3-methyl-1-triazeno) imidazole-4-carboxamide (MTIC), a potent alkylating agent. Recently, MTIC has been shown to alkylate DNA in the O6 of guanine and to be more cytotoxic in O6-AT deficient cells (Mer−) than in O6-AT proficient cells (Mer+) [9,10].
KeywordsSister Chromatid Exchange Human Glioma Cell Line Cellular Resistance Human Colon Tumor Cell Proficient Cell
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